Recently-identified, distinct subpopulations of midbrain dopamine (DA) neurons exhibit differences in their two primary in vivo activity patterns, tonic (single spike) firing and phasic bursting. These firing pat- terns, and transitions between them, are essential for driving axonal and dendritic dopamine release, and thus for controlling signal processing and behavioral functions of cortico-striatal circuits. We will show that the ionic mechanisms underlying these patterns, as well as the information content of these patterns, differ between DA subpopulations, with strong implications for behavioral control via distinct types of dopaminergic signaling. Aim 1 will uncover the biophysical mechanisms underlying the difference in tonic firing between the classic slow-firing and the more recently identified fast-firing DA neurons in the ventral tegmental area (VTA). These mechanisms likely also contribute to their distinct frequencies of burst firing in vivo. Aim 2 will elucidate the biophysical basis of bursts in the medial substantia nigra (SN), enabled by ATP-sensitive K+ (K-ATP) channels and necessary for novelty-induced exploration, versus bursts in the lateral SN that are controlled by Ca2+-activated SK K+ channels and may gate habitual motor sequences. Aim 3 will define the behavioral functions of two projection-specific DA subpopulations with the most distinctive in vivo firing patterns: the faster bursting VTA DA neurons projecting to the medial shell of the accumbens, which might be involved in salience or reward signaling, versus the medio-rostral SN DA neurons projecting to the lateral shell of the accumbens, which display continuous and slower bursting during novelty-mediated exploration. Differential biophysical control mechanisms of behaviorally-relevant firing patterns for distinct DA subpopulations may be selectively affected in the many known disorders of DA signaling, including addiction, schizophrenia and Parkinson's disease (PD). For example, a reduction in activity-dependent Ca2+ loading selective for SN DA neurons is a promising neuroprotective approach in PD. The further dissection of differences in the dynamics and molecular biophysics of both VTA and SN DA subpopulations proposed herein promises to lead to even more selectively tailored therapeutic strategies that tune the firing pattern in specific DA subpopulations. This project is based on recent, exciting advances in modeling the diversity of DA neurons in Dr. Canavier's lab that help explain the diversity of DA neurons pioneered by Dr. Roeper. The theoretical and computational approaches combine nonlinear dynamics and bifurcation analyses with morphologically realistic multi-compartmental modeling. Dr. Roeper's lab uses state of the art techniques, including retrograde tracing, adult mouse slice electrophysiology, channel-selective pharmacology, photoswitchable K-ATP blockers, and Dynamic Clamp, plus extracellular recordings and combined with juxtacellular labeling of single DA neurons with identified axonal projections in mice in vivo, to quantify the diversity of the DA populations in a comprehensive fashion, forming a synergistic loop for testing model predictions.